Associations of clonal hematopoiesis with recurrent vascular events and death in patients with incident ischemic stroke.

Clonal hematopoiesis (CH) is common among older people and is associated with an increased risk of atherosclerosis, inflammation, and shorter overall survival. Age and inflammation are major risk factors for ischemic stroke, yet the association of CH with risk of secondary vascular events and death is unknown. We investigated CH in peripheral blood DNA from 581 patients with first-ever ischemic stroke from the Prospective Cohort With Incident Stroke-Berlin study using error-corrected targeted sequencing. The primary composite end point (CEP) consisted of recurrent stroke, myocardial infarction, and all-cause mortality. A total of 348 somatic mutations with a variant allele frequency ≥1% were identified in 236 of 581 patients (41%). CH was associated with large-artery atherosclerosis stroke (P = .01) and white matter lesion (P < .001). CH-positive patients showed increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6), interferon gamma, high-sensitivity C-reactive protein, and vascular cell adhesion molecule 1. CH-positive patients had a higher risk for the primary CEP (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.04-2.31; P = .03), which was more pronounced in patients with larger clones. CH clone size remained an independent risk factor (HR, 1.30; 95% CI, 1.04-1.62; P = .022) in multivariable Cox regression. Although our data show that, in particular, larger and TET2- or PPM1D-mutated clones are associated with increased risk of recurrent vascular events and death, this risk is partially mitigated by a common germline variant of the IL-6 receptor (IL-6R p.D358A). The CH mutation profile is accompanied by a proinflammatory profile, opening new avenues for preventive precision medicine approaches to resolve the self-perpetuating cycle of inflammation and clonal expansion.

Effect of Mobile Stroke Unit Dispatch in all Patients with Acute Stroke or TIA.

OBJECTIVE: To determine the effect of additional mobile stroke unit (MSU) dispatch on functional outcomes among the full spectrum of stroke patients, regardless of subtype or potential contraindications to reperfusion therapies. METHODS: We used data from the nonrandomized Berlin-based B_PROUD study (02/2017 to 05/2019), in which MSUs were dispatched based solely on availability, and the linked B-SPATIAL stroke registry. All patients with final stroke or transient ischemic attack (TIA) diagnoses were eligible. The intervention under study was the additional dispatch of an MSU, an emergency physician-staffed ambulance equipped to provide prehospital imaging and thrombolytic treatment, compared to conventional ambulance alone. The primary outcome was the 3-month modified Rankin Scale (mRS) score, and the co-primary outcome was a 3-tiered disability scale. We identified confounders using directed acyclic graphs and obtained adjusted effect estimates using inverse probability of treatment weighting. RESULTS: MSUs were dispatched to 1,125 patients (mean age: 74 years, 46.5% female), while for 1,141 patients only conventional ambulances were dispatched (75 years, 49.9% female). After confounding adjustment, MSU dispatch was associated with more favorable 3-month mRS scores (common odds ratio [cOR] = 0.82; 95% confidence interval [CI]: 0.71-0.94). No statistically significant association was found with the co-primary outcome (cOR = 0.86; 9% CI: 0.72-1.01) or 7-day mortality (OR = 0.94; 95% CI: 0.59-1.48). INTERPRETATION: When considering the entire population of stroke/TIA patients, MSU dispatch improved 3-month functional outcomes without evidence of compromised safety. Our results are relevant for decision-makers since stroke subtype and treatment eligibility are unknown at time of dispatch. ANN NEUROL 2023;93:50-63.

A Managed Care System with Telemedicine Support for Neurological Emergencies.

OBJECTIVES: Telemedicine is frequently used to provide remote neurological expertise for acute stroke workup and was associated with better functional outcomes when combined with a stroke unit system-of-care. We investigated whether such system-of-care yields additional benefits when implemented on top of neurological competence already available onsite. METHODS: Quality improvement measures were implemented within a "hub-and-spoke" teleneurology network in 11 hospitals already provided with onsite or telestroke expertise. Measures included dedicated units for neurological emergencies, standardization of procedures, multiprofessional training, and quality-of-care monitoring. Intervention effects were investigated in a controlled study enrolling patients insured at 3 participating statutory health insurances diagnosed with acute stroke or other neurological emergencies. Outcomes during the intervention period between November 2017 and February 2020 were compared with those pre-intervention between October 2014 and March 2017. To control for temporal trends, we compared outcomes of patients with respective diagnoses in 11 hospitals of the same region. Primary outcome was the composite of up-to-90-day death, new disability with the need of ambulatory or nursing home care, expressed by adjusted hazard ratio (aHR). RESULTS: We included 1,418 patients post-implementation (55% female, mean age 76.7 ± 12.8 year) and 2,306 patients pre-implementation (56%, 75.8 ± 13.0 year, respectively). The primary outcome occurred in 479/1,418 (33.8%) patients post-implementation and in 829/2,306 (35.9%) pre-implementation. The aHR for the primary outcome was 0.89 (95% confidence interval [CI]: 0.79-0.99, p = 0.04) with no improvement seen in non-participating hospitals between post- versus pre-implementation periods (aHR 1.04; 95% CI: 0.95-1.15). INTERPRETATION: Implementation of a multicomponent system-of-care was associated with a lower risk of poor outcomes. ANN NEUROL 2023;93:511-521.

VISIT STROKE: non-inferiority of telemedicine-based neurological consultation for post-acute stroke patients - protocol of a prospective observational controlled multi-center study.

BACKGROUND: Telemedicine provides specialized medical expertise in underserved areas where neurological expertise is frequently not available on a daily basis for hospitalized stroke patients. While tele-consultations are well established in acute stroke assessment, the value of telemedicine-based ward-rounds in the subsequent in-patient stroke management is unknown. METHODS: Four telemedicine stroke networks in Germany, implemented in eight out of 16 federal states, participate in this prospective observational multi-center study. We plan to enroll 523 patients hospitalized due to acute (suspected or confirmed) stroke or transient ischemic attack. Each recruited patient will receive both a tele-consultation and an on-site consultation at the same day within the first three days after hospital admission. We will test non-inferiority of telemedicine-based assessments in ward-rounds in terms of quality of medical assessment and recommendations for hospitalized stroke patients. The correctness of the medical assessment and recommendation is defined as positive evaluation (binary, correct vs. in-correct) of six out of six predefined quality indicators by at least two out of three blinded independent raters. The non-inferiority margin for the difference in proportions of correct assessments is set to 5%-points. DISCUSSION: If non-inferiority of telemedicine-based ward-rounds compared to on-site ward-rounds by a neurologist were demonstrated, telemedicine-based neurological consultation for post-acute stroke patients may contribute to deliver evidence-based high-quality stroke care more easily in underserved regions. TRIAL REGISTRATION: DRKS - DRKS00028671 ( https://drks.de/search/de/trial/DRKS00028671 ; registration date 09-27-2022).

Patient-Centered Outcomes in a Randomized Trial Investigating a Multimodal Prevention Program After Transient Ischemic Attack or Minor Stroke: The INSPiRE-TMS Trial.

BACKGROUND: The INSPiRE-TMS trial (Intensified Secondary Prevention Intending a Reduction of Recurrent Events in Transient Ischemic Attack and Minor Stroke Patients) investigated effects of a multicomponent support program in patients with nondisabling stroke or transient ischemic attack. Although secondary prevention targets were achieved more frequently in the intensified care group, no significant differences were seen in rates of recurrent major vascular events. Here, we present the effects on prespecified patient-centered outcomes. METHODS: In a multicenter trial, we randomized patients with modifiable risk factors either to the intensified or conventional care alone program. Intensified care was provided by stroke specialists and used feedback and motivational interviewing strategies (≥8 outpatient visits over 2 years) aiming to improve adherence to secondary prevention targets. We measured physical fitness, disability, cognitive function and health-related quality of life by stair-climbing test, modified Rankin Scale, Montreal Cognitive Assessment, and European Quality of Life 5 Dimension 3 Level during the first 3 years of follow-up. RESULTS: Of 2072 patients (mean age: 67.4years, 34% female) assessed for the primary outcome, patient-centered outcomes were collected in 1,771 patients (877 intensified versus 894 conventional care group). Physical fitness improved more in the intensified care group (mean between-group difference in power (Watt): 24.5 after 1 year (95% CI, 5.5-43.5); 36.1 after 2 years (95% CI, 13.1-59.7) and 29.6 (95% CI, 2.0-57.3 after 3 years). At 1 year, there was a significant shift in ordinal regression analysis of modified Rankin Scale in favor of the intensified care group (common odds ratio, 1.23 [95% CI, 1.03-1.47]) but not after 2 (odds ratio, 1.17 [95% CI, 0.96-1.41]) or 3 years (odds ratio, 1.16 [95% CI, 0.95-1.43]) of follow-up. However, Montreal Cognitive Assessment and European Quality of Life 5 Dimension scores showed no improvement in the intensified intervention arm after 1, 2, or 3 years of follow-up. CONCLUSIONS: Patients of the intensified care program group had slightly better results for physical fitness and modified Rankin Scale after 1 year, but none of the other patient-centered outcomes was significantly improved. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01586702.

Cardiac Troponin and Recurrent Major Vascular Events after Minor Stroke or Transient Ischemic Attack.

OBJECTIVE: This study was undertaken to investigate whether high-sensitivity cardiac troponin T (hs-cTnT) is associated with major adverse cardiovascular events (MACE) in patients with minor stroke or transient ischemic attack (TIA), and whether this association differs after risk stratification based on the Age, Blood Pressure, Clinical Features, Duration of Symptoms, Diabetes (ABCD2 ) score. METHODS: INSPiRE-TMS was a randomized controlled trial allocating patients with minor stroke or TIA to an intensified support program or conventional care. In this post hoc analysis, participants were categorized using hs-cTnT levels (5th generation; Roche Diagnostics, Manheim, Germany; 99th percentile upper reference limit [URL] = 14ng/l). Vascular risk was stratified using the ABCD2 score (lower risk = 0-5 vs higher risk = 6-7). Cox proportional hazard regression was performed using covariate adjustment and propensity score matching (PSM) for the association between hs-cTnT and MACE (stroke/nonfatal coronary event/vascular death). RESULTS: Among 889 patients (mean age = 70 years, 37% female), MACE occurred in 153 patients (17.2%) during a mean follow-up of 3.2 years. hs-cTnT was associated with MACE (9.3%/yr, >URL vs 4.4%/yr, ≤URL, adjusted hazard ratio [HR] = 1.63 [95% confidence interval (CI) = 1.13-2.35], adjusted HR [Q4 vs Q1 ] = 2.57 [95% CI = 1.35-4.97], adjusted HR [log-transformed] = 2.31 [95% CI = 1.37-3.89]). This association remained after PSM (adjusted HR = 1.76 [95% CI = 1.14-2.72]). There was a significant interaction between hs-cTnT and ABCD2 category for MACE occurrence (pinteraction  = 0.04). In the lower risk category, MACE rate was 9.5%/yr in patients with hs-cTnT > URL, which was higher than in those ≤URL (3.8%/yr) and similar to the overall rate in the higher risk category. INTERPRETATION: hs-cTnT levels are associated with incident MACE within 3 years after minor stroke or TIA and may help to identify high-risk individuals otherwise deemed at lower risk based on the ABCD2 score. If confirmed in independent validation studies, this might warrant intensified secondary prevention measures and cardiac diagnostics in stroke patients with elevated hs-cTnT. ANN NEUROL 2021;90:901-912.

Association Between Dispatch of Mobile Stroke Units and Functional Outcomes Among Patients With Acute Ischemic Stroke in Berlin.

Importance: Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. Objective: To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. Design, Setting, and Participants: This prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only). Exposure: Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). Main Outcomes and Measures: The primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. Results: Of the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). Conclusions and Relevance: In this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global disability at 3 months. Clinical trials in other regions are warranted.

Predictive value of acute EEG measurements for seizures and epilepsy after stroke using a dry cap electrode EEG system - Study design and proof of concept.

The development of seizures is a common complication in patients with stroke. A recent study suggests that electroencephalography (EEG) could be useful to predict the occurrence of seizures after stroke. However, EEG is not routinely performed in the follow-up after stroke. We present the design and proof of concept of a large prospective cohort study in which we seek to evaluate the predictive usefulness of a single dry cap EEG measurement in the acute phase after stroke or transient ischemic attack (TIA) with respect to the development of poststroke epilepsy (PSE). In patients with ischemic stroke (IS), TIA, or intracerebral hemorrhage (ICH), an acute EEG measurement using a dry cap electrode EEG (dEEG) system is performed within 7 days of symptom onset. Electroencephalography data will be analyzed quantitatively and qualitatively looking for background asymmetry, different band power ratios, and epileptiform activity. The development of seizures will be assessed repeatedly during the first 2 years after stroke or TIA using a validated questionnaire. Results from the pilot phase of 11 patients showed that the dry cap EEG measurements in patients with acute stroke and TIA are feasible. In comparison with conventional EEG, a higher proportion of noise and artifacts was detected. This article is part of the Special Issue "Seizure & Stroke".

Effects of Prehospital Thrombolysis in Stroke Patients With Prestroke Dependency.

BACKGROUND AND PURPOSE: Data on effects of intravenous thrombolysis on outcome of patients with ischemic stroke who are dependent on assistance in activities of daily living prestroke are scarce. Recent registry based analyses in activities of daily -independent patients suggest that earlier start of intravenous thrombolysis in the prehospital setting leads to better outcomes when compared with the treatment start in hospital. We evaluated whether these observations can be corroborated in patients with prestroke dependency. METHODS: This observational, retrospective analysis included all patients with acute ischemic stroke depending on assistance before stroke who received intravenous thrombolysis either on the Stroke Emergency Mobile (STEMO) or through conventional in-hospital care (CC) in a tertiary stroke center (Charité, Campus Benjamin Franklin, Berlin) during routine care. Prespecified outcomes were modified Rankin Scale scores of 0 to 3 and survival at 3 months, as well as symptomatic intracranial hemorrhage. Outcomes were adjusted in multivariable logistic regression. RESULTS: Between February 2011 and March 2015, 122 of 427 patients (28%) treated on STEMO and 142 of 505 patients (28%) treated via CC needed assistance before stroke. Median onset-to-treatment times were 97 (interquartile range, 69-159; STEMO) and 135 (interquartile range, 98-184; CC; P<0.001) minutes. After 3 months, modified Rankin Scale scores of 0 to 3 was observed in 48 STEMO patients (39%) versus 35 CC patients (25%; P=0.01) and 86 (70%, STEMO) versus 85 (60%, CC) patients were alive (P=0.07). After adjustment, STEMO care was favorable with respect to modified Rankin Scale scores of 0 to 3 (odds ratio, 1.99; 95% confidence interval, 1.02-3.87; P=0.042) with a nonsignificant result for survival (odds ratio, 1.73; 95% confidence interval, 0.95-3.16; P=0.07). Symptomatic intracranial hemorrhage occurred in 5 STEMO versus 12 CC patients (4.2% versus 8.5%; P=0.167). CONCLUSIONS: The results of this study suggest that earlier, prehospital (as compared with in-hospital) start of intravenous thrombolysis in acute ischemic stroke may translate into better clinical outcome in patients with prestroke dependency. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02358772.

Influence of Distance to Scene on Time to Thrombolysis in a Specialized Stroke Ambulance.

BACKGROUND AND PURPOSE: Specialized computed tomography-equipped stroke ambulances shorten time to intravenous thrombolysis in acute ischemic stroke by starting treatment before hospital arrival. Because of longer travel-time-to-scene, time benefits of this concept are expected to diminish with longer distances from base station to scene. METHODS: We used data from the Prehospital Acute Neurological Treatment and Optimization of Medical Cares in Stroke (PHANTOM-S) trial comparing time intervals between patients for whom a specialized stroke ambulance (stroke emergency mobile) was deployed and patients with conventional emergency medical service. Expected times from base station to scene had been calculated beforehand using computer algorithms informed by emergency medical service routine data. Four different deployment zones with-75% probability-expected arrival within 4, 8, 12, and 16 minutes and total population coverage of ≈1.3 million inhabitants were categorized for stroke emergency mobile deployment. We analyzed times from alarm-to-arrival at scene, to start of intravenous thrombolysis and from onset-to-intravenous thrombolysis. RESULTS: Corresponding to the size of the respective catchment zone, the number of patients cared increased with distance (zone 1: n=30, zone 2: n=127, zone 3: n=156, and zone 4: n=217). Although time to stroke emergency mobile arrival increased with distance (mean: 8.0, 12.5, 15.4, and 18.4 minutes in zones 1-4), time from alarm-to-intravenous thrombolysis (mean: 41.8 versus 76.5; 50.2 versus 79.1; 54.5 versus 76.6; and 59.3 versus 78.0 minutes, respectively; all P<0.01) remained shorter in the stroke emergency mobile group across all zones. CONCLUSIONS: In a metropolitan area such as Berlin, time benefits justify a specialized stroke ambulance service up to a mean travel time of 18 minutes from base station. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01382862.

Copeptin Levels in Patients With Acute Ischemic Stroke and Stroke Mimics.

BACKGROUND AND PURPOSE: Copeptin levels are increased in patients diagnosed with stroke and other vascular diseases. Copeptin elevation is associated with adverse outcome, predicts re-events in patients with transient ischemic attack and is used in ruling-out acute myocardial infarction. We evaluated whether copeptin can also be used as a diagnostic marker in the prehospital stroke setting. METHODS: We prospectively examined patients with suspected stroke on the Stroke Emergency Mobile-an ambulance that is equipped with computed tomography and point-of-care laboratory. A blood sample was taken from patients immediately after arrival. We analyzed copeptin levels in patients with final hospital-based diagnosis of stroke or stroke mimics as well as in vascular or nonvascular patients. In addition, we examined the associations of symptom onset with copeptin levels and the prognostic value of copeptin in patients with stroke. RESULTS: Blood samples of 561 patients were analyzed. No significant differences were seen neither between cerebrovascular (n=383) and other neurological (stroke mimic; n=90) patients (P=0.15) nor between vascular (n=391) and nonvascular patients (n=170; P=0.57). We could not detect a relationship between copeptin levels and time from onset to blood draw. Three-month survival status was available in 159 patients with ischemic stroke. Copeptin levels in nonsurviving patients (n=8: median [interquartile range], 27.4 [20.2-54.7] pmol/L) were significantly higher than in surviving patients (n=151: median [interquartile range], 11.7 [5.2-30.9] pmol/L; P=0.024). CONCLUSIONS: In the prehospital setting, copeptin is neither appropriate to discriminate between stroke and stroke mimic patients nor between vascular and nonvascular patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862. The Pre-Hospital Acute Neurological Therapy and Optimization of Medical Care in Stroke Patients study (PHANTOM-S) was registered (NCT01382862). This sub-study was observational and not registered separately, therefore.

Improved prehospital triage of patients with stroke in a specialized stroke ambulance: results of the pre-hospital acute neurological therapy and optimization of medical care in stroke study.

BACKGROUND AND PURPOSE: Specialized management of patients with stroke is not available in all hospitals. We evaluated whether prehospital management in the Stroke Emergency Mobile (STEMO) improves the triage of patients with stroke. METHODS: STEMO is an ambulance staffed with a specialized stroke team and equipped with a computed tomographic scanner and point-of-care laboratory. We compared the prehospital triage of patients with suspected stroke at dispatcher level who either received STEMO care or conventional care. We assessed transport destination in patients with different diagnoses. Status at hospital discharge was used as short-term outcome. RESULTS: From May 2011 to January 2013, 1804 of 6182 (29%) patients received STEMO care and 4378 of 6182 (71%) patients conventional care. Two hundred forty-five of 2110 (11.6%) patients with cerebrovascular events were sent to hospitals without Stroke Unit in conventional care when compared with 48 of 866 (5.5%; P<0.01%) patients in STEMO care. In patients with ischemic stroke, STEMO care reduced transport to hospitals without Stroke Unit from 10.1% (151 of 1497) to 3.9% (24 of 610; P<0.01). The delivery rate of patients with intracranial hemorrhage to hospitals without neurosurgery department was 43.0% (65 of 151) in conventional care and 11.3% (7 of 62) in STEMO care (P<0.01). There was a slight trend toward higher rates of patients discharged home in neurological patients when cared by STEMO (63.5% versus 60.8%; P=0.096). CONCLUSIONS: The triage of patients with cerebrovascular events to specialized hospitals can be improved by STEMO ambulances. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01382862.

Dysfunctional action control as a specific feature of Parkinson's disease.

Parkinson's disease (PD) is characterised by motor deficits as well as cognitive alterations, particularly concerning frontal lobe control. Here, we were interested in whether executive function is abnormal already early in PD, as well as whether this dysfunction worsens as a part of the dementia in PD. The following groups engaged in tasks addressing action control: PD patients with mild and advanced motor symptoms (aPD) without dementia, PD patients with dementia (PDD), patients with Alzheimer's disease (AD) and healthy subjects (CON). Subjects either had to perform or inhibit button presses upon go and no-go cues, respectively. These cues were preceded by pre-cues, either randomly instructive of right or left hand preparation (switch condition), or repetitively instructive for one side only (non-switch condition). PDD and aPD omitted more go responses than CON. Furthermore, PDD disproportionally committed failures upon no-go cues compared to CON. In the non-switch condition, PDD performed worse than AD, whose deficits increased to the level of PDD in the switch condition. Over all PD patients, task performance correlated with disease severity. Under the switch condition, task performance was low in both PDD and AD. In the non-switch condition, this also held true for advanced PD patients (with and without dementia), but not for AD. Thus, the deficits evident in PDD appear to develop from imbalanced inhibitory-to-excitatory action control generally inherent to PD. These results specify the concept of dysexecution in PD and differentiate the cognitive profile of PDD from that of AD patients.

Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: a randomized clinical trial.

IMPORTANCE: Time to thrombolysis is crucial for outcome in acute ischemic stroke. OBJECTIVE: To determine if starting thrombolysis in a specialized ambulance reduces delays. DESIGN, SETTING, AND PARTICIPANTS: In the Prehospital Acute Neurological Treatment and Optimization of Medical care in Stroke Study (PHANTOM-S), conducted in Berlin, Germany, we randomly assigned weeks with and without availability of the Stroke Emergency Mobile (STEMO) from May 1, 2011, to January 31, 2013. Berlin has an established stroke care infrastructure with 14 stroke units. We included 6182 adult patients (STEMO weeks: 44.3% male, mean [SD] age, 73.9 [15.0] y; control weeks: 45.2% male, mean [SD] age, 74.3 [14.9] y) for whom a stroke dispatch was activated. INTERVENTIONS: The intervention comprised an ambulance (STEMO) equipped with a CT scanner, point-of-care laboratory, and telemedicine connection; a stroke identification algorithm at dispatcher level; and a prehospital stroke team. Thrombolysis was started before transport to hospital if ischemic stroke was confirmed and contraindications excluded. MAIN OUTCOMES AND MEASURES: Primary outcome was alarm-to-thrombolysis time. Secondary outcomes included thrombolysis rate, secondary intracerebral hemorrhage after thrombolysis, and 7-day mortality. RESULTS: Time reduction was assessed in all patients with a stroke dispatch from the entire catchment area in STEMO weeks (3213 patients) vs control weeks (2969 patients) and in patients in whom STEMO was available and deployed (1804 patients) vs control weeks (2969 patients). Compared with thrombolysis during control weeks, there was a reduction of 15 minutes (95% CI, 11-19) in alarm-to-treatment times in the catchment area during STEMO weeks (76.3 min; 95% CI, 73.2-79.3 vs 61.4 min; 95% CI, 58.7-64.0; P < .001). Among patients for whom STEMO was deployed, mean alarm-to-treatment time (51.8 min; 95% CI, 49.0-54.6) was shorter by 25 minutes (95% CI, 20-29; P < .001) than during control weeks. Thrombolysis rates in ischemic stroke were 29% (310/1070) during STEMO weeks and 33% (200/614) after STEMO deployment vs 21% (220/1041) during control weeks (differences, 8%; 95% CI, 4%-12%; P < .001, and 12%, 95% CI, 7%-16%; P < .001, respectively). STEMO deployment incurred no increased risk for intracerebral hemorrhage (STEMO deployment: 7/200; conventional care: 22/323; adjusted odds ratio [OR], 0.42, 95% CI, 0.18-1.03; P = .06) or 7-day mortality (9/199 vs 15/323; adjusted OR, 0.76; 95% CI, 0.31-1.82; P = .53). CONCLUSIONS AND RELEVANCE: Compared with usual care, the use of ambulance-based thrombolysis resulted in decreased time to treatment without an increase in adverse events. Further studies are needed to assess the effects on clinical outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01382862.

Prospective collection of blood plasma samples to identify potential biomarkers for the prehospital stroke diagnosis (ProGrEss-Bio): study protocol for a multicenter prospective observational study.

Introduction: Intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) are well-established, evidence-based, time-critical therapies that reduce morbidity and mortality in acute ischemic stroke (AIS) patients. The exclusion of intracerebral hemorrhage (ICH) is mandatory and has been performed by cerebral imaging to date. Mobile stroke units (MSUs) have been shown to improve functional outcomes by bringing cerebral imaging and IVT directly to the patient, but they have limited coverage. Blood biomarkers clearly distinguishing between AIS, ICH, and stroke mimics (SM) could provide an alternative to cerebral imaging if concentration changes are detectable in the hyperacute phase after stroke with high diagnostic accuracy. In this study, we will take blood samples in a prehospital setting to evaluate potential biomarkers. The study was registered in the German Clinical Trials Register (https://drks.de/search/de) with the identifier DRKS00023063. Methods and analysis: We plan a prospective, observational study involving 300 patients with suspected stroke and symptom onset of ≤4.5 h before the collection of biomarkers. Study participants will be recruited from three sites in Berlin, Germany during MSU deployments. The focus of the study is the collection of blood samples from participants at the prehospital scene and from participants with AIS or ICH at a second-time point. All samples will be analyzed using targeted and untargeted analytical approaches. Study-related information about participants, including medical information and discharge diagnoses from the subsequent treating hospital, will be collected and documented in an electronic case report form (eCRF). Discussion: This study will evaluate whether a single blood biomarker or a combination of biomarkers can distinguish patients with AIS and ICH from patients with stroke and SM in the early phase after symptom onset in the prehospital setting. In addition, the kinetics of blood biomarkers in AIS and ICH patients will be investigated. Our goal is to evaluate new ways to reliably diagnose stroke in the prehospital setting and thus accelerate the application of evidence-based therapies to stroke patients.

Optimization of sensitivity and specificity of a biomarker-based blood test (LVOCheck-Opti): A protocol for a multicenter prospective observational study of patients suspected of having a stroke.

Introduction: Acute ischemic stroke (AIS) is a time-critical medical emergency. For patients with large-vessel occlusions (LVO), mechanical thrombectomy (MT) is the gold-standard treatment. Mobile Stroke Units (MSUs) provide on-site diagnostic capabilities via computed tomography (CT) and have been shown to improve functional outcomes in stroke patients, but are cost-efficient only in urban areas. Blood biomarkers have recently emerged as possible alternative to cerebral imaging for LVO diagnosis. Prehospital LVO diagnosis offers the potential to transport patients directly to centers that have MT treatment available. In this study, we assess the accuracy of combining two biomarkers, HFABP and NT-proBNP, with clinical indicators to detect LVO using ultra-early prehospital blood samples. The study was registered in the German Clinical Trials Register (DRKS-ID: DRKS00030399). Methods and analysis: We plan a multicenter prospective observational study with 800 patients with suspected stroke enrolled within 24 h of symptom onset. Study participants will be recruited at three sites (MSUs) in Berlin, Germany. Blood-samples will be taken pre-hospitally at the scene and tested for HFABP and NT-proBNP levels. Additional clinical data and information on final diagnosis will be collected and documented in an electronic case report form (eCRF). Sensitivity and specificity of the combination will be calculated through iterative permutation-response calculations. Discussion: This study aims to evaluate the diagnostic capabilities of a combination of the biomarkers HFABP and NT-proBNP in LVO prediction. In contrast to most other biomarker studies to date, by employing MSUs as study centers, ultra-early levels of biomarkers can be analyzed. Point-of-care LVO detection in suspected stroke could lead to faster treatment in both urban and rural settings and thus improve functional outcomes on a broader scale. Clinical trial registration: Deutsches Register klinischer Studien https://drks.de/search/de/trial/DRKS00030399, DRKS00030399.

Protocol of the Berlin Long-term Observation of Vascular Events (BeLOVE): a prospective cohort study with deep phenotyping and long-term follow up of cardiovascular high-risk patients.

INTRODUCTION: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations. METHODS AND ANALYSIS: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes. ETHICS AND DISSEMINATION: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations. STUDY REGISTRATION: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021.